The effect of the therapeutic HIV vaccine, enhanced by a drug that unblocks the immune system

Studies on therapeutic HIV vaccines show significant progress, but they still do not allow us to do without antiretroviral treatment. Now, a study led by IrsiCaixa –a centre jointly promoted by the "la Caixa" Foundation and the Department of Health of the Generalitat de Catalunya– shows in the laboratory that the combination of a therapeutic vaccine with a treatment that reactivates the immune system enhances the response of the cells responsible for eliminating HIV. These results, published in the journal eBioMedicine, reinforce the idea that complete elimination of HIV will require a combination of multiple therapies and point to anti-PD-1 treatment as a promising tool to advance towards this goal. In addition, they stress the importance of combining vaccines and immunotherapies, as their summing effect can boost the immune system and make it better able to fight not only HIV, but also other viruses and diseases such as cancer.

The PD-1 molecule is found in the immune system's T cells and acts as a natural "brake" for the body. Its job is to prevent the immune system from attacking healthy cells in the body. "It is an essential self-protection mechanism, but in situations where we need very powerful immune activity it can work against us", explains Miguel Marín, a researcher at the University of Copenhagen and first author of the article during his PhD at IrsiCaixa. Anti-PD-1 treatments temporarily block this brake and prevent the generation of immune responses from being stopped. "We wanted to see if this therapy could help boost the immune responses induced by a therapeutic vaccine against HIV in people living with the virus", adds Marín.

More cells capable of recognizing and eliminating HIV

To test this, the team analyzed samples from people with HIV who had participated in the clinical trial of the therapeutic vaccine BCN01 and treated them in the laboratory with anti-PD-1. All of them had started antiretroviral treatment very early after diagnosis.

The results show that PD-1 blockade increases the number and functionality of HIV-specific CD8+ T cells generated by the vaccine. These cells are key to effectively identifying and destroying virus-infected cells. In addition, markers have been identified that indicate that these cells are activated and functional.

"Apart from people who started antiretroviral therapy early and who were also vaccinated, we also studied samples from people with the same clinical profile but not vaccinated. In these cases, anti-PD-1 therapy did not produce any increase in immune response. This suggests that the observed effect is due to the combination of the therapeutic vaccine and the anti-PD-1 treatment", says Julia Garcia-Prado, principal investigator at IrsiCaixa and leader of the study.

On the other hand, people treated in more advanced stages of HIV infection also showed an increase in virus-specific T cells after PD-1 blockade. However, they had other immune brakes, such as TIM-3, which should also be blocked together. This finding reinforces the potential of combining different immunotherapies depending on the stage of infection and the time of initiation of antiretroviral treatment.

Combination of strategies key to progress towards HIV elimination

The study also reveals that the greater the presence of PD-1 in CD8+ T cells, the stronger the response to the blockade of this molecule. This suggests that PD-1 could be used as a biomarker to identify people who could benefit from this type of treatment after vaccination.

Taken together, the results reinforce the importance of combining vaccines and immunotherapies, as they can exert a synergistic effect and achieve much more effective responses. In this case, immunotherapy improves the response to the therapeutic HIV vaccine, but previous studies have also shown the reverse effect: people with cancer who receive immunotherapy respond better to treatment if they have previously been vaccinated. This combination of both strategies, which primes the immune system to respond more effectively, has enormous potential in multiple fields, from infectious diseases to cancer.

"We know that HIV is a very complex virus and that its cure will not depend on a single route, but on the sum of different approaches", says García-Prado, who stresses that anti-PD-1 therapy, in combination with the therapeutic vaccine, could be one of them.